Cardiac overexpression of metallothionein rescues cold exposure-induced myocardial contractile dysfunction through attenuation of cardiac fibrosis despite cardiomyocyte mechanical anomalies

Free Radic Biol Med. 2012 Jul 15;53(2):194-207. doi: 10.1016/j.freeradbiomed.2012.04.005. Epub 2012 May 5.


Cold exposure is associated with an increased prevalence of cardiovascular disease although the mechanism is unknown. Metallothionein, a heavy-metal-scavenging antioxidant, protects against cardiac anomalies. This study was designed to examine the impact of metallothionein on cold exposure-induced myocardial dysfunction, intracellular Ca(2+) derangement, fibrosis, endoplasmic reticulum (ER) stress, and apoptosis. Echocardiography, cardiomyocyte function, and Masson trichrome staining were evaluated in Friend virus B (FVB) and cardiac-specific metallothionein transgenic mice after cold exposure (3 months, 4 °C). Cold exposure increased plasma levels of norepinephrine, endothelin-1, and TGF-β; reduced plasma NO levels and cardiac antioxidant capacity; enlarged ventricular end-systolic diameter; compromised fractional shortening; promoted reactive oxygen species (ROS) production and apoptosis; and suppressed the ER stress markers Bip, calregulin, and phospho-eIF2α, accompanied by cardiac fibrosis and elevated levels of matrix metalloproteinases and Smad-2/3 in FVB mice. Cold exposure-induced echocardiographic, histological, ER stress, ROS, apoptotic, and fibrotic signaling changes (but not plasma markers) were greatly improved by metallothionein. In vitro metallothionein induction by zinc chloride ablated H(2)O(2)- but not TGF-β-induced cell proliferation in fibroblasts. In summary, our data suggest that metallothionein protects against cold exposure-induced cardiac anomalies possibly through attenuation of myocardial fibrosis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Calcium / metabolism
  • Cold Temperature / adverse effects
  • Endoplasmic Reticulum Stress
  • Endothelin-1 / blood
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Fibrosis / diagnostic imaging
  • Fibrosis / etiology
  • Fibrosis / metabolism
  • Fibrosis / pathology
  • Friend murine leukemia virus / genetics
  • Gene Expression
  • Male
  • Metallothionein / genetics
  • Metallothionein / metabolism*
  • Mice
  • Mice, Transgenic
  • Myocardial Contraction*
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology
  • Norepinephrine / blood
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • Stress, Physiological
  • Transforming Growth Factor beta / blood
  • Ultrasonography


  • Endothelin-1
  • Reactive Oxygen Species
  • Transforming Growth Factor beta
  • Metallothionein
  • Calcium
  • Norepinephrine